The matrix metalloproteinases (MMPs) are neutral metalloproteinases and zinc (Zn.sup.2+) is essential in the active site for their activation. They degrade collagen, laminin, proteoglycans, fibronectin, elastin, gelatin etc. under physiological conditions and therefore, are effective on growth and tissue remodeling of articulation tissue, bone tissue and connective tissue. At least 10 classes of MMPs which differ in primary structure are identified. As common characteristics of these enzymes, MMPs
(1) have Zn.sup.2+ in the active site and the activity depends on calcium (Ca.sup.2+), PA0 (2) are secreted as an inactive proenzyme and activated outside of cells, PA0 (3) have high homology on amino acid sequence, PA0 (4) have an ability to degrade various extracellular matrix components in vivo, PA0 (5) are regulated by tissue inhibitors of metalloproteinases (TIMP) which are specific to MMPs. PA0 (1) via an acyl halide, PA0 (2) via a mixed acid anhydride, PA0 (3) using a condensing agent.
Recently, it is reported that gelatinases, neutral metalloproteinases classified in MMPs which degrade various extracellular matrix represented by gelatin are related to various diseases.
Gelatinase inhibitors are useful for prevention and/or treatment of various diseases induced by overexpression or excess activation of gelatinases. Such diseases are, for example, rheumatoid diseases, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis of, invasion of or growth of tumor cells, autoimmune diseases (e.g. Crohn's disease, Sjogren's syndrome), diseases caused by vascular emigration or infiltration of leukocytes, arterialization.